2-(2-halo-3,4-dimethoxybenzyl)-5-(4-methoxyphenyl)-oxazolidines

ABSTRACT

New intermediates, namely 2-(2-halo-3,4-dimethoxybenzyl)-5-(4-methoxyphenyl)-oxazolidines, are prepared by a synthetic sequence which uses a Darzen&#39;s reaction in a homogeneous solvent system.

This is a division of application Ser. No. 909,759 filed Sept. 16, 1986,now U.S. Pat. No. 4,705,862 which is a continuation of application Ser.No. 657,904, filed Oct. 5, 1984, now abandoned.

This invention relates to new intermediates and processes which areuseful for preparingN-[2-hydroxy-2-(4'-methoxyphenyl)ethyl]-2-(2-halo-3,4-dimethoxyphenyl)-ethylamines. The latter compounds are, in turn, chemical intermediates whichare known to be useful for preparing certain dopaminergic andanti-hypertensive agents such as fenoldopam, U.K. Pat. No. 1,595,502 orU.S. Pat. No. 4,197,297.

The overall reaction sequence which uses this invention is illustratedas follows: ##STR1##

In the reaction sequence above, X is chloro or fluoro.

The Darzen's homologation reaction, as is known to the art, involvesreaction of an aldehyde with a α-halo lower alkyl alkanoate in thepresence of an acid binding agent, such as an alkali metal loweralkoxide, to give a glycidic acid ester. This ester is, then,saponified, usually with aqueous alkali. The resulting glycidic acid isrearranged, following decarboxylation, in the presence of acid to givethe homo aldehyde.

C. R. Johnson et al., J. Org. Chem. 47 1205 (1982), report that the lowand uncertain yields of the homo products of the Darzen's reaction maybe due to premature hydrolysis of the ester reagent and subsequentformation of a halohydrin by-product. Most often, the reactionconditions of the prior art Darzen's reactions involve a biphase orsolid-solvent system, for example U.K. Pat. No. 1,094,238. Either thehigh cost of chemical or low through-put of the reaction, which arereported for various prior art modifications which have been suggestedto improve yields of the Darzen's reaction, precludes commercial use ofthe reaction in many instances.

The prior art, therefore, reports uncertain, usually low, yields of thedesired higher homologous product using the Darzen's reaction.

We have now discovered that, with Darzen's homologation of a2-halo-3,4-dimethoxybenzaldehyde, good and predictable yields, from 90to 95%, are obtained using a homogeneous solvent system such as reactingthe two starting materials, with an excess of the ester such as methylchloro- or bromoacetate, in methylene chloride in the presence of aconcentrated solution of an alkali metal C₁₋₄ -alkoxide in a loweralkanol, such as methanol. Temperature is maintained at from -20° to 5°C.

The hydrolysis is then carried out at about 20°-25° C. by adding aqueousalkali, such as a concentrated sodium or potassium hydroxide aqueoussolution, to the reaction mixture. 50% Sodium hydroxide solution ispreferred. The product is the preferred trans sodium salt of theglycidic acid which is produced in situ in quantitative yield to be usedfor the following decarboxylation. The water-methylene chloride systemis taken to pH 5 with acid at 30° C. for two to five hours to rearrangeand decarboxylate the glycidic acid in good yield to produce the desiredphenylacetaldehyde (4).

The methylene chloride-water mixtures which are necessarily used in thehydrolysis-rearrangement steps tend to form emulsions which make theisolation of the desired phenylacetaldehyde (4) difficult. Unexpectedly,addition of a small quantity of a phase transfer catalyst has solvedthis problem. For example, between 0.5 to 1.5%, by weight, of catalystbased on the benzaldehyde, is added when ethyl triphenyl phosphoniumiodide is the catalyst. Slightly larger quantities, up to 3%, may benecessary when benzyl triphenyl phosphonium chloride, benzyl triethylammonium chloride or tetrabutyl phosphonium chloride are used. TheDarzen's step on a 12 liter scale starting with2-chloro-3,4-dimethoxybenzaldehyde gave the end product secondary amine(7) ih which X is chloro, in 57.5% overall yield with no trace of theadded catalyst.

The 2-halo-3,4-dimethoxyphenylacetaldehyde (4) is reacted with astoichiometric excess of 2-(4'-methoxyphenyl)-1-aminoethanol (5) in alower alkanol at a temperature from the range of 10 to 10° . Thetemperature of this reaction is not as critical as are others of thereaction sequence described herein but, since the next reaction iscarried out at a low temperature, the given range is conveniently usedfor oxazolidine formation. We have found that the equilibrium of thereaction is displaced toward the oxazolidine when a mole ratio of 1 to1.4, acetaldehyde/aminoethanol, is used.

The new intermediate of structure 6 is a part of this invention. The2-(2-halo-3,4-dimethoxybenzyl)-5-(4-methoxyphenyl) -oxazolidine may beoptionally isolated but is most often used in situ. The oxazolidine isformed in situ as a mixture of substantially equal quantities of cis andtrans isomers which both react in the next step of the reaction. Theformation of the oxazolidine intermediate is very quick and complete.

The methanolic reaction mixture which contains the oxazolidine (6) is,then, treated with an excess of an organometallic reducing agent, suchas sodium borohydride, at below 10° C. followed by a period of roomtemperature, to give the desiredN-[2-hydroxy-2-(4-methoxyphenyl)ethyl]-2-(2-halo-3,4-dimethoxyphenyl)ethylamine (7). This product is isolated by methods known to the art and isthen cyclized by methods described in the prior art to give a compoundof formula 8.

The following examples illustrate the operation of this invention. Alltemperatures are Centigrade.

EXAMPLE 1 A. General Overall Pilot Procedure

Step 1. Preparation of 2-chloro-3-hydroxy-4-methoxybenzaldehyde

Chlorine gas is introduced into a solution of3-hydroxy-4-methoxybenzaldehyde in N,N-dimethylformamide at -10° to -30°C. When the addition of chlorine is complete, the reaction mixture isstirred at -25° C. for 30 minutes and, then, poured into water. Theproduct is separated by filtration and washed with water. The wetproduct may te dried or used directly in the next step. Average yield,73%.

Step 2. Preparation of 2-chloro-3,4-dimethoxybenzaldehyde (1)

To a solution of 2-chloro-3-hydroxy-4-methoxybenzaldehyde inN,N-dimethylformamide/water, solid potassium carbonate and dimethylsulfate are added. After heating for a further hour, the solution iscooled and poured into water. The product is separated by filtration andwashed with water. The wet product may be dried or used directly in step6 below. Average yield without purification, 96%.

Step 3. Preparation of 1-(4-methoxyphenyl)-2-nitroethanol

To a cooled solution of nitromethane in methanol is added4-methoxybenzaldehyde. Sodium methoxide solution is then added slowlywith stirring keeping the temperature below 20° C. A thick, white slurryof the nitronate salt is formed which is stirred for a further two hoursat a temperature between 10° and 20° C. The mixture is acidified withacetic acid, and methylene chloride and distilled water are added. Theproduct is extracted into the methylene chloride layer, washed withwater, and the aqueous layer discarded. The methylene chloride isdistilled off under vacuum. The resulting reddish-orange oil is readyfor use in the next step. Average yield, 75%.

Step 4. Preparation of 1-(4-methoxyphenyl)-2-aminoethanol acetate

A solution of the nitroethanol in methanol is treated with glacialacetic acid and a slurry of 5% palladium-on-charcoal in methanol. Thesealed reaction vessel is pressurized to a low pressure with hydrogenand agitated vigorously. The temperature of the reaction mixture is keptbelow 60° C. When the hydrogen uptake is complete, the reaction vesselis cooled to 20°-30° C. and the catalyst filtered off. After distillingoff the methanol under reduced pressure, the residue is redissolved inethyl acetate and the volume of solution reduced by distillation undervacuum. The precipitate is spun dry, washed with ethyl acetate and thendried at approximately 40° C. Average yield, 70%.

Step 5. Preparation of 1-(4-methoxyphenyl)-2-aminoethanol (5)

Method A

A suspension of the acetate in methylene chloride is treated withaqueous sodium hydroxide until the pH of the water layer is greater than9.5. The layers are separated and the methylene chloride layer washedwith 10% aqueous sodium hydroxide. The methylene chloride is distilled,then replaced with toluene. Upon complete removal of the methylenechloride the toluene is allowed to cool. The precipitate formed isisolated by filtration, washed with toluene followed by pet ether, andvacuum dried. This free base is suitable for use in the condensationstep hereafter described. Average yield, 93%.

Method B

To a suspension of methanol-washed Amberlite IRA-400 resin in methanolis added a methanol solution of 1-(4-methoxyphenyl)-2-amino ethanolacetate. The slurry is stirred at 10° to 20° C. for about an hour andfiltered to remove the resin. The methanol filtrate is filtered andconcentrated. The concentrate is suitable for use in the condensation.

Step 6. Preparation of 2-chloro-3,4-dimethoxy-phenyl- acetaldehyde (4)

To a stirred solution of methylene chloride, 2-chloro-3,4-dimethoxybenzaldehyde from above and excess methyl chloroacetate at -20° C., isadded 25% methanolic sodium methoxide. The reaction is stirred at -10°C. to 20° C. for three hours, then 50% aqueous sodium hydroxide is addedover 1.5 hours. After an additional 30 minutes, de-ionized water isadded. The pH is adjusted to approximately 5.0 by the addition of 6Nhydrochloric acid. The pH is maintained at approximately 5.0 by additionof hydrochloric acid as needed. The reaction is stirred for two to fourhours at 30°-35° C. The reaction mixture is allowed to settle, then theaqueous layer separated and re-extracted with methylene chloride. Thecombined methylene chloride extracts are washed with water, sodiumbicarbonate, and again with water. The methylene chloride is removedfrom the organic extract at reduced pressure and replaced with methanol.This methanolic solution of the acetaldehyde is suitable for use in thecondensation step.

Step 7. Preparation ofN-[2-hydroxy-2-(4'-methoxethyl]-2-(2-chloro-3,4-dimethoxyphenyl)ethylamine(7)

Method A

The methanolic solutions of the acetaldehyde from Step 6 and theaminoethanol from Step 5 are mixed and stirred at 0° C. one hour. Sodiumborohydride is added in small portions and the temperature maintainedbelow 10° C. The mixture is stirred and allowed to warm to 24° C. oversix hours. The reaction mixture is cooled to 15° C. and filtered to give(7) as a white solid. Average yield from the benzaldehyde (1), 55%.

Method B

The methanol solution of 1-(4-methoxyphenyl)-2-aminoethanol from step 5and 2-chloro-3,4-dimethoxy-phenylacetaldehyde from step 6 are cooled toabout 10° C. and treated with sodium borohydride. The reaction isstirred four to six hours. The methanol is removed under vacuum. Thereaction product is acidified and extracted into methylene chloride. Themethylene chloride solution is washed with base and concentrated. Theconcentrate is treated with ethyl acetate and the product isolated as awhite solid suitable for use in step 8.

Step 8. Preparation of 6-chloro-7,8-dimethoxy-1-(4'-methoxyphenYl)-2,3,4,5-tetrahydro-lH-3-benzazepine hydrobromid

Method A

A solution of 7 is stirred for one hour in a cooled solution of 98%methanesulfonic acid in methylene chloride. Deionized water is added,then the mixture neutralized by slowly adding concentrated ammoniumhydroxide solution until the pH reaches 9.0, taking care that thetemperature does not exceed 25° C. The aqueous layer is separated anddiscarded. The methylene chloride solution is washed with distilledwater, then distilled off. The residue is dissolved in ethyl acetate,cooled, and hydrogen bromide passed into the solution keeping thetemperature between 10° and 20° C. The solution is stirred overnight at5°-10° and the hydrobromide salt separated by centrifugation, washedwith cold ethyl acetate and dried at 55° C. to give the titled product.

B. Chemical requirements for 50 gallon reaction run of the describedsteps:

    ______________________________________                                        Chemical               Quantity                                               ______________________________________                                        (1)  methylene chloride    75 L                                               (2)  2-chloro-3,4-dimethoxybenzaldehyde                                                                  15 Kg (75 g-moles)                                 (3)  methyl chloroacetate  11.25 Kg                                                                      (106 g-moles)                                      (4)  sodium methylate solution (25%)                                                                     18.75 L; 17.7 Kg                                                              (82 g-moles)                                       (5)  liquid caustic soda (50%)                                                                           8.0 Kg                                             (6)  methylene chloride    20 L                                               (7)  water, deionized      4.8 L                                              (8)  hydrochloric acid (18%)                                                                             13.1 L, (more if                                                              required to pH 5)                                  (9)  methylene chloride, and water,                                                                      20 L methylene                                          first aqueous extract chloride                                                                      10 L water                                         (10) methylene chloride, second                                                                          20 L                                                    aqueous extract                                                          (11) water, deionized first backwash                                                                     20 L                                               (12) sodium bicarbonate solution (6%),                                                                   1.1 Kg bicarbonate                                      second backwash       19 L water                                         (13) water, deionized, final backwash                                                                    20 L                                               (14) methanol              48 L                                               (15) methanol              90 L                                               (16) 1-(4-methoxyphenyl)-2-amino-                                                                        to be determined as                                     ethanol               35 mole % over the                                                            acetaldehyde                                       (17) sodium borohydride    1.2 Kg                                             (18) methanol              40 L                                               ______________________________________                                    

EXAMPLE 2 Structure of the Oxazolidine Intermediate

A solution of 2-(4-methoxyphenyl)-1-amino ethanol (0.334 g, 0.02 mole)in 2 mL CDCl₃ was added to a solution of2-chloro-3,4-dimethoxyphenylacetaldehyde (0.428 g, 0.02 mole) in 2 mL ofCDCl₃. The CDCl₃ solution was dried over magnesium sulfate and filtered.Spectral data were obtained by both proton NMR and carbon NMR methods.The chloroform solutions were diluted with methanol and treated withsodium borohydride and filtered to give the secondary amine (7) in a 60%yield.

The 360 MHz proton nuclear magnetic resonance spectrum of the productdemonstrated two sets of doublets between 4.8-4.9 ppm which integratefor two protons. This, with the lack at imine proton resonance at 7-9ppm, is determinative of the structure of the intermediate. A C₁₃nuclear magnetic resonance spectrum shows an equal mixture of cis andtrans-isomers.

EXAMPLE 3 Use of a Phase Transfer Aqent

To a stirred solution of 2-chloro-3,4-dimethoxy benzaldehyde (800 g, 4mole) and methyl chloroacetate (640 g, 5.9 mole) in 4 L of methylenechloride at -20° C. was added 25% sodium methoxide (1.0 L, 4.4 mole).The reaction was stirred between 5°-15° C. for 21/2 hours and 50% sodiumhydroxide (480 g) was added over 1 hour. After an additional 1/2 hours,water (250 mL) was added and the pH adjusted to 5 with 20% hydrochloricacid. The pH was maintained at 5 by slowly adding additionalhydrochloric acid solution for 3 hours at 30°-35° C. The reaction wasallowed to settle. The aqueous layer was separated and re-extracted withmethylene chloride. The combined methylene chloride extracts were washedwith 1.5 L of water. The methylene chloride layer was washed with 1.2 Lof 5% sodium carbonate solution with 6.4 g of ethyltriphenylphosphoniumiodide added to break the emulsion. The methylene chloride was washedwith 1.5 L of water with an additional 6.4 g ofethyltriphenylphosphonium iodide added to break the emulsion. Themethylene chloride was removed under reduced pressure and replaced withmethanol. The methanol solution was added to 1-(4-methoxyphenyl)-2aminoethanol (850 g, 5.0 mole) in 8 L of methanol at 0° C. Afterstirring for 1 hr, sodium borohydride (120 g, 3.24 mole) was addedcarefully. The reaction was stirred for 6 hrs, cooled, and filtered togive 841 g ofN-[2-hydroxy-2-(4'-methoxyphenyl)ethyl]-2-(2-chloro-3,4-dimethoxyphenyl)ethylamine as a white solid. Assay 99.9%.

What is claimed is:
 1. A compound of the formula (1): ##STR2## in whichX is chloro or fluoro.
 2. A compound according to claim 1 which is2-(2-chloro-3,4-dimethoxybenzyl)-5-(4-methoxyphenyl)-oxazolidine.